3/11/2017 CONGENITAL DIAPHRAGMATIC HERNIA Robyn Barst Pediatric PH - - PowerPoint PPT Presentation

3/11/2017 1 COMPREHENSIVE ANALYSIS OF PERSISTENT PULMONARY HYPERTENSION IN CONGENITAL DIAPHRAGMATIC HERNIA

Rachel K. Hopper, MD March 11, 2017 Robyn Barst Pediatric PH Research & Mentoring Grant

CONGENITAL DIAPHRAGMATIC HERNIA

• Developmental defect of the diaphragm,

characterized by lung hypoplasia

• “Dual hit” hypothesis:
• Compression of lungs during development
• Developmental program leading to abnormal lung

parenchyma and pulmonary vasculature

• Associated morbidity and mortality
• Spectrum of severity

Keijzer et al, Am J Pathol. 2000 Pierro and Thébaud. Semin Fetal Neonat Med. 2014

MULTIFACTORIAL ETIOLOGY OF PH

• Delayed transition – “PPHN”
• Present early, can resolve
• Lung hypoplasia
• Decreased cross-sectional area of the vascular bed
• Vascular anomalies
• Existing vessels are abnormal
• Increased circulating vasoconstrictors
• Affects function of existing vessels
• Left heart disease/obstruction
• Small left sided structures, aortic valve stenosis,

coarctation of the aorta pulmonary venous hypertension

LUNG ABNORMALITIES IN CDH

Normal (6 mo) CDH (7 mo)

Images courtesy Marcus Davey, PhD

PA

Aw Aw

PA PA = pulmonary artery AW = airway

3/11/2017 2

SEVERE PERSISTENT PH

CDH (7 mo) CDH (3 mo)

Images courtesy Marcus Davey, PhD, Kudakwashe Chikwava, MBBCh.

• A subset of patients with severe PH
• Increased muscularization, intimal hyperplasia,

similar to PAH

• Mechanisms and risk factors unclear

STUDY AIMS

1) Determine the prevalence and clinical risk factors for persistent PH in CDH

• Retrospective cohort study of 322 patients with CDH at

CHOP from 2005-2015

• Assess PH over time by blinded review of serial

echocardiograms in first year of life

• Determine clinical risk factors for persistent PH using

existing clinical research database

2) Determine whether rare genetic variants increase the risk of PH in CDH

• Whole exome sequencing (WES) to assess for genetic

variants associated with PH at 6 months of age

HYPOTHESIS

• PH persists in a significant subset of infants

with CDH

• Persistent PH in CDH is multifactorial in

etiology

• Clinical factors (prenatal indices, postnatal insults)
• Genetic variants (PAH genes?)
• Understanding these risk factors is necessary to

improve clinical prediction and treatment

7

PRELIMINARY DATA

• N=265 CDH infants (322 total) from 2005-2015
• High incidence of PH early, resolves in most
• Nearly 30% continue to have at least moderate PH,

defined by echo or PH treatment, at 6 months of age

.2 .4 .6 .8 1 Probability of PH severity 50 100 150 200 250 300 350 400 450 500 Age at Echo (days)

Probability of PH severity by Age at ECHO

Probability of PH by age

Probability of PH by age

3/11/2017 3 PRELIMINARY DATA

• Intrathoracic liver position associated with

persistent PH

• Defect side, fetal lung volumes, LHR not associated
• Plan to assess additional clinical factors

GENETIC ANALYSIS

• Collaboration with CHOP Center for Applied

Genomics

• Whole exome sequencing (WES) of 24 patients

with CDH and persistent PH

• Preliminary analysis identified 23 potential

pathogenic variants enriched in our population

• Plan for additional sequencing for validation

and compare to CDH without PH

PRELIMINARY WES DATA THANK YOU

• Pulmonary Hypertension Association
• Dr. Robyn Barst
• Mentors and collaborators:
• Brian Hanna, MDCM, PhD
• Steven Kawut, MD, MS
• Hakon Hakonarson, MD, PhD
• Holly Hedrick, MD